Optimization of a binding fragment targeting the “enlarged methionine pocket” leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors
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Acknowledgments
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI084004 and R01AI097177. We acknowledge the support of a Fulbright Fellowship to X.B.-A. We thank Stewart Turley and Robert Steinfeldt for providing support for the X-ray data collection and computing environment at the Biomolecular Structure Center of the University of Washington. Crystallography performed in support of
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2021, Journal of Biological ChemistryCitation Excerpt :This work also presents the mode of action of two diaryldiamine MetRS1 inhibitors that interact with XcMetRS, thus revealing the structural basis for selectivity of these compounds between type 1 and type 2 MetRS. Although the binding mode of the diaryldiamines to XcMetRS is reminiscent to that of type 1 MetRS, where the inhibitors also occupy the enlarged methionine and auxiliary pockets (34–38, 48, 58, 59), our structural data revealed amino acid differences between XcMetRS and type 1 MetRS both in the methionine and auxiliary pockets, particularly P257 and Y237, which could account for the lower binding affinity of the diaryldiamines to XcMetRS. Accordingly, the XcMetRS Y237L mutant showed increased susceptibility to REP8839 inhibition, as predicted from the structure.
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